Sympathetic ganglion stimulation method for treatment of hyperhidrosis, raynauds phenomenon, cerebral ischemia, asthma and hypertension

ABSTRACT

Methods for treatment of hyperhidrosis, Raynaud&#39;s phenomenon, cerebral ischemia and asthma and hypertension by nerve stimulation are disclosed. In particular, the invention relates to the improvement of these conditions by stimulating at least one ganglion selected from the group consisting of T-1 through T-4 ganglia, cervical ganglia, renal nerve or combinations thereof with an implantable, wireless, battery-less and lead-less stimulator. Stimulations of the ganglion may be carried out with pulsed radiofrequency, thermal energy or optical irradiation.

RELATED APPLICATIONS

This application is related to and claims priority to U.S. ProvisionalApplication No. 61/625,830, filed on Apr. 18, 2012, entitled“Application of RF Chip Implant in Treating Primary Focal Hyperhidrosisand Related Conditions and Device Thereof,” which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

The invention relates to methods for treatment of hyperhidrosis,Raynaud's phenomenon, cerebral ischemia, asthma and hypertension bypulsed radiofrequency nerve stimulation. In particular, the inventionrelates to the improvement of these conditions by stimulating at leastone ganglion selected from the group consisting of T-1 through T-4ganglia, cervical ganglia, renal ganglia or combinations thereof with awireless, battery-less and lead-less stimulator.

BACKGROUND OF THE INVENTION

Hyperhidrosis: Hyperhidrosis refers to profuse perspiration (excessivesweating) beyond the body's thermoregulatory needs. It is believed thatan estimated 2-3% of Americans suffer from excessive sweating of theunderarms (axillary hyperhidrosis) or the palms and soles of the feet(palmoplantar hyperhidrosis). For the purpose of discussion thatfollows, palmar hyperhidrosis (excessive sweating of the palms) will bestressed. Sweaty palms disorder is embarrassing, can hamper businessinteractions and cause social anxiety. Severe cases of palmarhyperhidrosis also have serious consequences, prohibiting peoplesuffering from such a disorder to shake hands, lift any objects or workin professions that require contact with electricity.

Primary palmar hyperhidrosis is caused by overactivity of thesympathetic nervous systems, largely triggered by emotional stressesincluding anxiety, nervousness, anger and fear. Sympathetic nervoussystem is one of two major parts of the autonomic nervous system, theother being the parasympathetic system. In cases of palmarhyperhidrosis, the stellate ganglion and the first, second, third andforth thoracic ganglia of the sympathetic nerve chain are believed toplay the major role in the abnormal signal generation to sweat glands ofthe palms.

There are various treatments available for palmar hyperhidrosis.Aluminum chloride is used in antiperspirants. However, patients sufferedfrom hyperhidrosis require antiperspirants in high concentration toeffectively treat the symptoms of the condition. Anticholinergic drugshave direct effect on sympathetic nervous systems although they haveside effects. Botulinum injection on affected area may block neuralcontrol of sweat glands. However, such a treatment is expensive andshort-term, with patients requiring to receive injection every 6 to 12months.

Removal or destruction of sweat gland is one surgical option availablefor hyperhidrosis although such a treatment has many side effects.Endoscopic transthoracic sympathectomy (ETS), a minimally invasivesurgical procedure, involves resection or clamping of the thoracicganglion on the main sympathetic chain. Particularly, an en blocablation by laser vaporization of the T2 ganglion has proven to yield apermanent therapeutic effect for palmar hyperhidrosis. However, ablationof the targeted nerve cluster has a host of complications, includingcompensatory sweating, bradycardia, hypersensitive to light, lack ofnorepinephrine and acetylcholine, and possibly nerve regeneration.Clamping of the thoracic ganglion is intended to permit the reversal ofthe ablation procedure so as to minimize the aforementionedcomplications. However, it has shown that effective clamping also causesirreversible damages to the nerve, and patients continue to suffersimilar side effects such as compensatory hyperhidrosis.

Electrical stimulation of the sympathetic nerve chain has been proposedto treat hyperhidrosis. The principle behind such approach involvesdisruption and modulation of hyperactive neuronal circuit transmissionat specific sites in the sympathetic nerve chain. The procedure is alsosaid to minimizes or possibly eliminate the complications from ETS.Currently, electrical stimulation of the nerve is usually carried out bysurgically implanting a generator in the vicinity of the targeted nervecluster, and then applying electrical modulation to the nerve throughelectrodes that are connected to the generator by lead. Conventionalstimulation device, however, bears significant shortcomings. Forexample, the implantable generator requires a battery or power source,which means the size of the device cannot be too small. Also, anextension lead, containing electric wire, is attached to the generatorand carries the electric pulses to the electrode that is attached to thenerves or tissues. This lead is undesirable as it may tangle with ordisturb the nearby organs. If damaged, a leak and possibly more severecomplications may occur as a result.

It is therefore the goal of the present invention to provide a treatmentmethod for palmar hyperhidrosis by employing a miniature, battery-lessstimulator that requires no extension lead.

Raynaud's phenomenon: Raynaud's phenomenon is a disorder of the bloodvessels, usually in the fingers and toes. It is a condition in whichcold temperature or emotional stress causes blood vessel spasms thatblock blood circulation to the fingers and toes. Specifically, Raynaud'sphenomenon is a hyperactivation of the sympathetic nervous systemcausing extreme vasoconstriction of the peripheral blood vessels, leadto tissue hypoxia. Typical symptoms are pain within the affectedextremities, discoloration, and sensations of cold and/or numbness. Thedisorder can be distressing and in severe cases, dangerous when someonewith Raynaud's is placed in cold climate.

Treatment for Raynaud's phenomenon may include prescription medicinessuch as nifedipine or diltiazem, though it has the usual side effects ofheadache, flushing, and ankle edema. An ETS can be performed by ablatingthe nerves that signal the blood vessels of the fingertips to constrict.But complications common to ETS would also occur.

Cerebral ischemia: cerebral ischemia is a medical disorder where thereis insufficient blood flow to the brain to meet metabolic demand.Typically ischemia occurs when one of the arteries that brings blood toa part of the brain is blocked by a blood clot or a cholesterol plague.The resulting lack of oxygen or cerebral hypoxia leads to death of braincells or ischemic stroke. Cerebral ischemia is a leading cause of adultdisability in the United States, killing nearly 150,000 people eachyear.

Tissue plasminogen activator (TPA) is an effective medication that lysesa clot and possibly restores blood circulation to the affected area ofthe brain. However, administering TPA has a very limited time window ofonly 3-4 hours. TPA also may not be suitable for patients with certainconditions, such as tendency to bleed, heart problems or diabetics,because there is the potential risk of serious brain bleed. Surgery,such as carotid endarterectomy, may also be performed on patientssuffering from brain ischemia. The procedure aims to unlock carotidarteries, which supply blood to the brain, that have accumulated plaqueor fat buildup in them. However, the inherent dangers of such surgicalprocedure prompt other safer and less invasive approach for thetreatment of cerebral ischemia

Asthma: Asthma is a chronic lung disorder that inflames and narrows theairways. The inner walls of an asthmatic's airways are swollen orinflamed. This swelling and inflammation makes the airways extremelysensitive to irritations and increases one's susceptibility to anallergic reaction.

Most asthma medications work by relaxing bronchospasm. Treatment isusually with an inhaled short-acting beta-2 agonist and oralcorticosteroids. Side effects such as insomnia, anxiety, increased heartrate and tremor occur in some patients taking asthmatic medications.

Hypertension: Hypertension is a medical condition in which the bloodpressure in the arteries is elevated. An elevation of blood pressureincreases the risk of developing cardiac disease, renal disease,atherosclerosis or arteriosclerosis, eye damage and stroke. It isestimated that hypertension affects approximately one in three adults inthe U.S., —73 million people—clearly a serious public health problem.

Abnormally elevated sympathetic nerve activity is found to contribute tothe progression of hypertension and renal disease. Therefore,hypertension, renal and heart failure can be treated by reducing thesympathetic efferent or afferent nerve activity of the kidneys.Medication such as rennin-angiotensin system inhibitors, calcium channelblockers or diuretics have been used to treat hypertension.

The causes of the prevalent diseases discussed herein can all be relatedto abnormal activities of the sympathetic nerve chain. Therefore, novelmethods of treating these diseases are presented to reduce theside-effects associated with the conventional approaches.

SUMMARY OF THE INVENTION

The present invention discloses methods of treating physiologicaldisorders caused by abnormality of sympathetic activities by implantinga pulsed radiofrequency stimulator at specific locations along thesympathetic chain of the patient.

In an embodiment, the invention provides a method of treatinghyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma andhypertension by positioning an implantable, lead-less and battery-lessstimulator proximate to at least one ganglion along the sympatheticnerve chain wherein the stimulator is configured to be wirelesslycontrolled and charged, monitoring the electrical states of the at leastone ganglion and the stimulator, applying pulsed radiofrequency to theganglion, and adjusting the stimulation parameters of the pulsedradiofrequency based on the monitored electrical states until thesymptoms of the disease have been alleviated. For hyperhidrosis,Raynaud's phenomenon, cerebral ischemia and asthma, this involvespositioning the stimulator proximate to the inferior portion of thestellate ganglion, and over T2-T4. For hypertension, this involvespositioning the stimulator proximate to the renal ganglia.

According to the present invention, the stimulation parameters comprisepulse frequency, pulse width duration, current amplitude, voltageamplitude, duty cycle and waveform of the pulsed radio frequency. Theelectrical states of the ganglion comprise the bio-impedance of theganglion being stimulated. The electrical states of the stimulatorcomprise voltage level, current amplitude, impedance and temperature ofthe stimulator.

In an embodiment, the method of treating hyperhidrosis, Raynaud'sphenomenon, cerebral ischemia, asthma and hypertension further includesthe step of monitoring the physiological states of a patient. Thephysiological states comprise heart rate, body and tissue temperatures,blood pressure and blood oxygen level of the patient. Based on themonitored physiological states, the stimulation parameters of the pulsedradiofrequency may be adjusted.

In an embodiment, the method of treating hyperhidrosis, Raynaud'sphenomenon, cerebral ischemia, asthma and hypertension further includesthe step of transmitting the monitored electrical and/or physiologicalstates to a remote controller outside the patient body. The remotecontroller may adjust the stimulation parameters of the pulsedradiofrequency based on the monitored electrical and/or physiologicalstates until the symptoms of the diseases have been alleviated. Theremote controller may also be configured to wirelessly charge thestimulator.

In an embodiment, the invention provides a method of treatinghyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma andhypertension by positioning an implantable, lead-less and battery-lessstimulator proximate to at least one ganglion along the sympatheticnerve chain wherein the stimulator is configured to be wirelesslycontrolled and charged. The method further involves applying thermalenergy to the ganglion via the stimulator until the symptoms of thediseases have been improved.

In addition to the embodiments describe so far, the invention furtherprovides a method of treating a disease of a human patient diagnosedwith at least one of hyperhidrosis, Raynaud's syndrome, cerebralischemia, asthma or hypertension by positioning an implantable,lead-less and battery-less stimulator proximate to at least one ganglionalong the sympathetic nerve chain wherein the stimulator is configuredto be wirelessly controlled and charged. The method further involvesapplying optical irradiation to the ganglion via the stimulator untilthe symptoms of the diseases have been alleviated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 compares the pulsed radiofrequency waveform with the continuousradiofrequency waveform.

FIG. 2 is a schematic illustration of a patient having an endoscopicinsertion site in the second or third intercostals space at the anterioraxillary line.

FIG. 3 is a partial exposed view of the hemithorax displaying theendoscopic system incising the parietal pleura to expose the sympatheticnerve chain.

FIG. 4 is an expose view of the thoracic ganglia with the implantablestimulator positioned for pulse radiofrequency treatment.

FIG. 5 illustrates implantable stimulators sutured on targetedsympathetic ganglion.

FIG. 6 is a schematic diagram illustrating an implantable stimulatorcapable of providing pulsed radiofrequency according to an embodiment ofthe present invention.

FIG. 7 illustrates an embodiment of the wireless, battery-less andlead-less stimulator in one stand-alone package.

FIG. 8 is a schematic diagram illustrating an implantable stimulatorcapable of providing thermal energy according to an embodiment of thepresent invention.

FIG. 9 is a schematic diagram illustrating an implantable stimulatorcapable of providing thermal optical irradiation to an embodiment of thepresent invention.

DETAILED DESCRIPTION

In the following description, reference is made to the accompanyingfigures that form a part hereof, and in which are shown by way ofillustration the several embodiments of the invention. It is to beunderstood that other embodiments are contemplated and may be madewithout departing from the scope or spirit of the present invention. Thefollowing disclosure is therefore not to be interpreted in a limitingsense. Rather, the scope of the invention is to be defined in accordancewith the appended claims.

Novel method and apparatus have been developed to regulate sympatheticnerve activity to improve the conditions of a patient diagnosed with atleast one of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia,asthma or hypertension. Particularly, the method involves surgicallyimplanting a wireless, battery-less and lead-less stimulator in theproximity of at least one ganglion along the sympathetic nerve chain,and applying pulsed radiofrequency (PRF) stimulations to the targetedganglion until the symptoms are improved.

The efficacy of PRF treatment in nerve disorders has been welldocumented. In general, there are two types of PRF procedures. The firstinvolves applying continuous radiofrequency (RF) to the targeted tissue,while the other involves using PRF. Biological changes in tissue duringelectrical stimulation can occur due to thermal effects, the highintensity electric fields, or as a result of both. PRF applies shortpulses of RF signals from a pulse generator to the tissue. The heatproduced during these pulses depends on the power deposition. In PRF,because the pulse duration is only a small percentage of the timebetween pulses, the average tissue temperature rise for the same RFvoltage is much less for PRF than for continuous RF, as illustrated inFIG. 1. Thus, higher voltages can be applied in a PRF procedure than arecommonly used in RF without raising the tissue temperature into thedenaturation range above 45° C. Recent studies also suggest that PRFoperating at high frequency with sinusoidal waveform can better reducethermal damage to the nerve, as compared to RF stimulation.

The sympathetic nervous system (SNS) is part of the autonomic nervoussystem, which also includes the parasympathetic system. The SNSactivates the flight-or-fight response, and operates through a series ofinterconnected neurons.

There are two kinds of neurons involved in the transmission of anysignal through the SNS: pre- and post-ganglionic. Sympathetic neurons ofthe spinal cord (or preganglionic neurons) communicate with peripheralsympathetic neurons (or postganglionic neurons) via a series ofsympathetic ganglia. Within the ganglia, preganglionic neurons joinpostganglionic neurons through chemical synapses. At synapses within thesympathetic ganglia, preganglionic sympathetic neurons releaseacetylcholine, a chemical messenger (or neurotransmitter) that binds andactivates nicotinic acetycholine receptors on postganglionic neurons.And in response, postganglionic neurons (with two notable exceptions)release noradreanline, which activates adrenergic receptors on theperipheral tissues.

The exceptions mentioned above are postganglionic neurons of sweatglands and chromaffin cells of the adrenal medulla. Postganglionicneurons of sweat glands release acetylcholine for the activation ofmuscarinic receptors. Chromaffin cells, act like postganglionic neurons,synapse with preganglionic neurons and stimulate the chromaffin torelease norepinephrine and epinephrine directly into the blood.

Sympathetic nerves originate inside the vertebral column, toward themiddle of the spinal cord in the intermediolateral cell column (orlateral horn), beginning at the first thoracic segment of the spinalcord and are thought to extend to the second or third lumbar segments.Because its cells begin in the thoracic and lumbar regions of the spinalcord, the SNS is said to have a thoracolumbar outflow. Axon (or nervefiber), is a long, slender projection of a nerve cell, or neuron, thattypically connects electrical impulses away from the neuron's cell body.Axon of the sympathetic nerves leave the spinal cord in ventral branches(rami) of the spinal nerves, and then separate out as “white rami” whichconnects to two ganglia extending alongside the vertebral column on theleft and right.

The axons of the autonomic nerve cells in the nuclei of the cranialnerves, in the thoracolumbar lateral comual cells, and in the greymatter of the sacral spinal segments are called preganglionicsympathetic nerve fibers, while those in ganglion cells are termedpostganglionic sympathetic nerve fibers. The postganglionic sympatheticnerve fibers converge in ganglia that are located alongside thevertebral bodies in the neck, chest, and abdomen. Specifically, thestellate ganglion is located laterally adjacent to the intervertebralspace between the seventh cervical and first thoracic vertebrae. Thefirst, second third and forth thoracic ganglia lie next to theirrespective vertebral bodies on either side of the thoracic cavity.

Physiological disorders associated with abnormal sympathetic nerveactivity may be treated with electrical stimulation of the appropriateganglia outside of the spinal column. In the present invention, thepreferred effect is to use an implantable stimulator to modulate nerveactivities with pulsed radiofrequency (PRF). Reference of the term“stimulate” or “stimulation” in this disclosure means application of PRFsignal that may be either excitatory or inhibitory to a sympatheticganglion affected by such signal. Proper PRF stimulation prevents thetotal destruction of the ganglion, thereby offers the advantage over theirreversible en bloc ablation procedure.

As used herein a stimulator is positioned “proximate to” or “in theproximity of” a sympathetic ganglion means a stimulator placed at a sitecapable of producing a direct PRF effect on tissue that if stimulatedwould result in the alleviation of the diseases' symptoms. By way of anexample, a stimulator may be placed either directly on the tissue orabout 10 mm or less from the tissue.

As use herein “adjusting stimulation parameters of pulsedradiofrequency” means adjusting pulse frequency, pulse width duration,current amplitude, voltage amplitude, repetition rate, duty cycle and/orpulse waveform of the pulsed radiofrequency.

A variety of approaches are available for upper thoracic implantation ofstimulator. The common procedures are: posterior paravertebral thoracicsympathectomy, thoracoscopic sympathectomy and retroperitoneal lumbarsympathectomy. The preferred implantation method of the presentinvention is accomplished percutaneously using an endoscope system.

The implanting procedure starts with placing the patient under generalanesthesia and intubated with a double lumen endotracheal tube. Thedouble lumen endotracheal tube allows alternating one-lung ventilation.A single micro incision, preferably no longer than 5 mm, is made in thesecond or third intercostals space at the anterior axillary line that isidentified as insertion site 101, as shown in FIG. 2. Now referring toFIG. 3, a 5 mm-diameter endoscope 102 is inserted through the insertionsite 101 into the thoracic cavity 103. Identification of the first andsecond ribs, the targeted ganglia (T1-T4), the azygos vein, thebrachiocephalic and subclavian arteries, and the parietal pleura isperformed. The sympathetic nerve chain is visualized as theganglionated, longitudinal cord structure located at the junction of theribs and the vertebral bodies.

A wireless, battery-less and lead-less stimulator capable of generatingPRF is then inserted via the insertion site 101 to a predeterminedlocation along the sympathetic nerve chain that is associated with thephysiological disorder being treated, as shown in FIG. 4. For palmarhyperhidrosis, the stimulator is preferably placed in the proximity ofthe T2 and T3 ganglia. Palmar skin perfusion (PSP) and palmar skintemperature (PST) of the patient are monitored to verify that thecorrect ganglion is being stimulated. The stimulation parameters of thePRF may be further adjusted by the stimulator itself or wirelessly by aseparate remote controller until proper PSP and PST responses arereceived. Once the symptom of the disorder is improved, the stimulatormay be directly sutured or clamped to the nearby tissue or parietalpleura, as shown in FIG. 5. Because the stimulator of the presentinvention is lead-less, the operating surgeons need not be concernedwith lead migration or lead direction out of thoracic cavity as found inthe prior art methods. Because the stimulator is further configured tobe wirelessly powered, there is also no concern with power cable.Implanting an entirely stand-alone stimulator significantly simplifiesand shortens the surgical procedure. A topical skin adhesive is used toclose the tiny single incision after the stimulator is sutured oraffixed. Upon completion of one side of the body, the other side is thendone in similar fashion.

The stimulator employed in the present invention may also comprise anelectrical sensor means that monitor electrical states of the ganglionand the stimulator. For example, impedance magnitude may be determinedby the stimulator due to tissue regeneration of the stimulated ganglionor electrode encapsulation. Circuit parameters may be regulatedinternally by the stimulator's preprogrammed rules. The stimulator mayalso comprise a physiological sensor means that monitor thephysiological states of the patient. Physiological factors such as bodyand tissue temperatures, heart rate, blood pressure or blood oxygenlevel of the patient may be determined. Accordingly, the treatmentmethod of the present invention may further include a step of monitoringthe electrical states of the ganglion and the stimulator. A further stepof monitoring the physiological states of the patient may also bepreformed. According to the monitored states, another step of adjustingthe stimulation parameters of the PRF may be undertaken until thesymptoms of the diseases are demonstrably relieved.

Electrical nerve stimulation involves applying an energy signal (pulse)at a certain frequency to the neurons of a nerve. The energy signalcauses depolarization of neurons inside the nerve above the activationthreshold, resulting in an action potential. The energy applied is afunction of the current/voltage amplitude and pulse width duration. Inthe present invention, to effectively treat the aforementionedphysiological disorders, the current/voltage amplitude of the PRF may beoperated at a voltage between 1 volt and 60 volts. Preferably, PRF isapplied at a low amplitude of 5 volts in sinusoidal waveform tostimulate the targeted ganglion without irreversibly damaging the nerve.The pulse frequency may be in the range of 10 KHz to 10 MHz, preferablyset at 500 KHz. Repetition rate of the PRF may be operated at between0.1 Hz and 10 Hz, preferably at 2 Hz. Pulse width duration is betweenabout 0.1 ms and 500 ms, preferably set at 50 ms. These PRF parametersranges are generally found to be effective in treating disorders such ashyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma andhypertension.

An alternative embodiment of the present invention involves usingthermal energy to stimulate at least one ganglion along the sympatheticnerve chain until the symptoms of the diseases are demonstrativelyalleviated. Particularly, a stimulator capable of applying thermalstimulation is percutaneously implanted in the proximity of the targetedganglion. The stimulator may include thermal means that can produce a“cooling effect” on the sympathetic ganglion and its nearby tissue.Sympathetic outflow may be suppressed by directly cooling the ganglionwith the stimulator of the present invention until its associated nervesensitivity and metabolic activities are substantially diminished. Inoperation, nerve body may be cooled from normal body temperature, about37° C., preferably down to 5° C., by the present stimulator withoutpermanently damaging the ganglion. Conversely, the stimulator mayinclude thermal means that can heat the sympathetic ganglion in order toexcite its associated nerve and metabolic activities. Preferably, theheating may be carried out in the temperature range of 37° C., to 65° C.without permanently damaging the ganglion.

Another embodiment of the present invention involves applying opticalirradiation to stimulate targeted sympathetic ganglion. Althoughelectrical stimulation of nerves is quite effective, it comes withcomplications such as damage caused by the physical contact from theelectrodes and the inability to stimulate with absolute precision,thereby causing undesired stimulation of the nearby tissues. Opticalenergy such as laser allows more controlled and selective spatialresolution of stimulation than electrical stimulation. Laser producescoherent light that has radiation waves that are in alignment with eachother and are typically of a single wavelength. To achieve effectiveoptical irradiation, the neurons must be driven at adequate rate toproduce safe, reproducible action potentials.

In the present invention, a stimulator equipped with a light sourcedriver and a plurality of diodes may be implanted near the sympatheticganglion to evoke desired neural activity. Low-level laser diode orlight-emitting diodes may be employed. Particularly, low-level, pulsednear infrared laser light may be used to elicit neural activation of theassociated sympathetic ganglion. In one embodiment, a pulsed diodelaser, with wavelength in the range of 1000 nm to 2000 nm, pulseduration in the range of about 1 ms to about 20 ms and repetition ratein the range of 1 Hz-10 Hz may be used to stimulate the ganglion untilsymptoms of the associated disorder are alleviated.

The following examples discuss each of the physiological disorders thatmay be treated by the stimulation method of the present invention bygrouping the relevant ganglia associated with the disorder and thepreferred parameters of the PRF used.

EXAMPLE 1

PRF stimulation may be applied to treat hyperhidrosis. Patients who aresuffering from palmar hyperhidrosis or other forms of hyperhidrosis arefound to have abnormal sympathetic activities with the T2 and T3ganglia.

To treat palmar or axillary hyperhidrosis, the wireless, battery-lessand lead-less stimulator is implanted over the inferior stellateganglion and over upper thoracic ganglia. Preferably, the stimulator ispositioned over the T2 and T3 ganglia. A rapid PRF that exceeds thenatural cycling rate of the nerve polarization and depolarization(overpacing) is applied to the T2 and T3 ganglia until the nerve and itsneurotransmitters are fatigued so that no signals can be furtherconducted. The PRF should be operated at a frequency of 500 KHz, currentamplitude at 5 volts, repetition rate at 2 Hz, and pulse width durationat 50 ms. PSP and PST of the patient are monitored before, during andafter PRF stimulation until the symptom of the palmar hyperhidrosis isalleviated.

EXAMPLE 2

Raynaud's phenomenon is a vasospastic disorder triggering discolorationof the fingers, toes and occasionally other areas. The disorder iscaused by increased activation of sympathetic noradrenergic nervescontrolling muscle tone of digit arteriolar walls.

Treatment of Raynaud's phenomenon is akin to the procedures conductedwith patients suffering from palmar hyperhidrosis. PRF stimulation inthe form of overpacing is applied to the T2 and T3 ganglia until symptomis improved. Preferably, the PRF should be operated at a frequency of500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, andpulse width duration at 50 ms. Temperatures of the fingers are monitoredbefore, during and after the PRF stimulation.

EXAMPLE 3

The cerebral blood vessels, particularly the pial vessels, have anabundance of non-adrenergic sympathetic nerve distribution thatoriginates in the cervical ganglia and follows the carotid artery toproject into the ipsilateral hemisphere. The intracerebral vesselsconstrict when sympathetic nerve is excited and dilated when thesefibres are interrupted. Stellate ganglion block has shown to improvecerebral perfusion by reducing the cerebral vascular tone.

The first thoracic sympathetic ganglion fuses with the inferior cervicalganglion to make the stellate ganglion. Stellate ganglion sits at thetop end of the sympathetic chain in front of the C7 vertebra of theneck. For the treatment of cerebral ischemia, a wireless, battery-lessand lead-less stimulator is surgically implanted over the stellateganglion. PRF in the form of overpacing is applied to inhibitsympathetic outflow. Preferably, the PRF should be operated at afrequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2Hz, and pulse width duration at 50 ms. Physiological conditions of thepatient, such as heart rate and blood pressure, should be monitoredbefore, during and after the procedure.

EXAMPLE 4

Sympathetic activities of the lower cervical and upper thoracicsympathetic ganglia may affect the tracheal, bronchial, and pulmonarysystems. Therefore, proper PRF stimulation of the lower cervical andupper thoracic sympathetic ganglia may be conducted to treat asthma byalleviating the contraction of the smooth muscles of the airways.

Particularly, positioning a PRF stimulator in the proximity of T2 to T4ganglia may help treating patients suffering from asthma. Adjusting theparameters of the stimulator to drive (increase) sympathetic output hasproven to relax the airways. Preferably, the PRF should be operated at afrequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2Hz, and pulse width duration at 0.1 ms, until the symptom of the asthmahas relieved. Physiological conditions of the patient, such as heartrate and blood pressure, should be monitored before, during and afterthe procedure.

EXAMPLE 5

Untreated hypertension can lead to central nervous complications such asstroke and vascular dementia. Patients suffering from hypertension maybe found to have renal disease or abnormal renal function. An effectiveway to treat hypertension may involve controlling the afferent nervesignals from the kidney to the brain and blocking efferent nerve stimulifrom entering the kidney.

A PRF stimulator of the present invention is used for renal denervationto reduce sympathetic nerve outflow. The stimulator is positioned in theproximity of renal artery, preferably in the region of T5 through T12ganglion. PRF in the form of overpacing is applied to the targeted siteuntil symptom of hypertension is demonstrably improved. Preferably, thePRF should be operated at a frequency of 500 KHz, current amplitude at 5volts, repetition rate at 2 Hz, and pulse width duration at 50 ms.Systematic blood pressure and heart rate are monitored before, duringand after the PRF stimulation.

Conventional electrical stimulator typically comprise a pulse generatorcapable of producing electric stimulation signals which are sent totargeted nerve by insulated leads coupled to the spinal cord by one ormore electrodes. The pulse generator can either be implanted inside thepatient or left outside the body. For temporary treatment where thepulse generator is left outside the patient body, an introducer equippedwith electrode on the tip is surgically inserted and positioned in thevicinity of the targeted nerve. The proximal end of the introducer isleft outside of the body and connected to a pulse generator. For theimplanted application, an introducer is used to position the stimulationlead, which is affixed to the targeted tissue and left in place afterthe introducer is withdrawn. The lead is then connected to the pulsegenerator that is implanted somewhere in the body. A pulse generatorused in the implanted application is usually equipped with a battery forpower.

Lead is a device used to access the nerve targeted for stimulation. Itis typically a bundle of electrically conducting wires insulated fromthe surrounding by a non-electrically conducting coating. The wires ofthe lead connect the pulse generator to the stimulation electrodes,which transfers the energy pulse to the nerve. Leads may be conventionalpercutaneous leads or paddle-type leads. Depending on the locations ofthe nerve and the pulse generator, the length of the lead usually rangesfrom 10 cm to 30 cm. Electrodes are conductive terminals, usually at theend of the lead, that may contact the nerve directly or contact tissuesadjacent to the nerve. Electrodes can have different geometricconfigurations and can induce an electric field that affects the nerveactivities. Electrodes are generally made with platinum (pt), gold (Au),titanium (Ti), stainless steel, or alloy.

The present invention discloses a novel implantable stimulator which iswireless, battery-less and lead-less. FIG. 6 is a schematic diagramillustrating one embodiment of the present invention. As shown in FIG.6, the stimulator includes a telemetric CMOS chip 100, a coil 200, and aplurality of stimulating electrodes 180. The stimulator ispercutaneously implanted in the proximity of the targeted ganglia 500for PRF stimulation.

The plurality of electrodes 180, the coil 200, and the telemetric CMOSchip 100 are electrically interconnected and housed in one stimulatorpackage. The size of the stimulator, which requires no battery and isimplemented using CMOS technology, is no bigger than a microscopic chip.Preferably, the size of the stimulator shall not exceed 5 mm×15 mm. Apower source 300, configured within a remote controller 400, wirelesslypowers the CMOS chip 100 via the coil 200. Power may be transmitted byinductive coupling or any other wireless charging mechanisms such aselectromagnetic induction coupling, resonate inductive coupling,capacitive coupling, light (optical, laser), or radio frequency charging(e.g., 900 MHz band or radio or microwave). A preferred embodiment ofthe power source 300 may be a Class-E power amplifier, which provideshigher power transmission efficiency than other conventional poweramplifiers. Generally, high-frequency signals have shorter skinpenetration than low-frequency signals. The preferred embodiment here isto use 1 MHz wireless signals to power the CMOS chip 100 of thestimulator.

A remote controller 400, which houses the power source 300, the receiver301 and the feedback controller 302, is configured to locate outside ofpatient body and away from the implanted stimulator. In addition tobeing a wireless power source for the implanted stimulator, the remotecontroller 400 may also receive signals transmitted from the CMOS chip100, and vice versa. The remote controller 400 may adjust thestimulation parameters of the PRF based on the received signals andtransmit renewed parameter commands to the CMOS chip 100 until thesymptoms of the diseases are improved. Note that in the presentinvention no wire is needed to connect the remote controller 400 withthe CMOS chip 100. In one embodiment, the remote controller 400 maylocate up to 7 cm from the implanted stimulator. The remote controller400 may also be implemented in preexisting device such as a mobilephone, a tablet, a laptop computer or any mobile equipment. Byconfiguring the remote controller within a preexisting device, thepatient may conveniently control and charge the implanted stimulatorwithout further carrying an additional device

Referring to FIG. 6, the CMOS chip 100 may comprise elements such as:rectifier 110, voltage regulator 120, PRF generator 130, multiplexer140, RF signal receiver 150, micro-controller 160, transmitter 170,analog digital converter 180, physiological sensor 190, and electricalsensor 191.

In operation, wireless power provided by remote controller 400 may berectified by rectifier 110 to convert the wireless power to directcurrent. Voltage regulator 120 may regulate the direct current to obtainsteady voltage and remove signal noise. Rectifier 110 may also sendcurrent directly to the PRF generator to generate pulsed radiofrequency.

The stimulator of the present invention further comprises an electricalsensor means for monitoring the electrical states of the ganglion andthe CMOS chip. The electrical sensor 191 may monitor the bio-impedanceof the ganglion that is being stimulated. It may also measure theelectrical and functional states of the CMOS chip 100, for examples thevoltage level, current amplitude, impedance, and chip temperature.

The stimulator of the present invention may further comprise aphysiological sensor means for monitoring the physiological states ofthe patient being treated. The physiological sensor 190 may monitor thetissue and body temperatures, heart rate, blood pressure, blood oxygenlevel and/or other physiological states of the patient. In oneembodiment of the present invention, the physiological sensor 190 mayinclude a measuring means that can clamp or cuff to a blood vessel nearthe ganglion to allow measurement of the physiological states of thepatient. The measuring means may be in any shape or size as long as itcan clamp to a blood vessel.

The micro-controller 160 receives the monitored states from the sensors190 and 191, and may adjust the stimulation parameters of the PRFaccording to preprogrammed protocols. Stimulation parameters mayinclude: pulse frequency, pulse width duration, current/voltageamplitude, repetition rate, duty cycle and/or waveform. In anotherembodiment, the monitored states received by the sensors 190 and 191 maybe transmitted by transmitter 179 to the receiver 301 of the remotecontroller 400. The remote controller 400 may adjust the stimulationparameters based on the monitored states and then transmit modulatedparameter instructions to the RF signal receiver 150 of the CMOS chip100. In one embodiment, the remote controller 400 may be configured todisplay the electrical states of the CMOS chip 100 and the ganglion orthe physiological states of the patient for ease of controlling the PRFstimulation parameters.

The present invention further teaches an implantable wireless andbattery-less stimulator that requires no lead. FIG. 7 illustrates oneembodiment of the present invention. This novel stimulator devicecombines a plurality of electrodes 13, the CMOS chip 10 and the powerreceiver 11 in one stand-alone package which simplifies the implantingprocedure as well as eliminates disturbance of tissues caused by lead.Under the stimulator package 14, the CMOS chip 10 may be placed on asubstrate layer 12 support by a component 15. The component 15 may be acapacitor, a thermal source driver, an optical source driver and/or thesensor means. Power receiver 11 may be configured to couple the CMOSchip 10 inside the stimulator package 14 to minimize the stimulatorsize. The plurality of electrodes 13 may be configured to evenly spaceapart around the stimulator package 14 or in any fashion that canprovide optimal contact with the nerve tissue. On the circuit level, asshown in FIG. 6, the PRF generator 130 of the CMOS chip 100 connects tothe electrodes 180 via the multiplexer 140. In structure, the electrodes13, surrounding the stimulator package 14 without leads, stimulate thetargeted ganglion by applying appropriate PRF. The present inventionremoves the extension leads that connect electrodes with the stimulatorin the prior art systems. A complete lead-less system may avoid problemssuch as lead fracture or lead leakage found in a lead-based system. Itcan also simplify implant procedure by allowing simple insertion of asingle stand-alone stimulator in the proximity of the targeted ganglionwithout concerning lead anchoring, lead migration or lead disturbance.The stimulator embodiment illustrated in FIG. 7 also may be sutureddirectly to the nerve or nearby tissues such as pleura.

In another embodiment, the plurality of electrodes may be replaced witha plurality of thermal conductors or optical diodes, depending on theconfigurations of the CMOS chip inside the stimulator. Note that theshape of the stimulator package is not limited. Any package that canhouse the CMOS chip, power receiver and the plurality ofelectrodes/thermal conductors/light diodes in one stand-alone packagefalls under the scope of the present disclosure.

The stimulator of the present invention may further comprise a fasteningmeans to help secure the stimulator to the nerve or nearby tissues. Thefastening means may be in the form of a clamp, claw, cuff or any otherconfigurations to facilitate securing of the stimulator. The fasteningmeans may also be configured as the measuring means for thephysiological sensor to help monitoring the physiological states of thepatient.

To permit safe implantation, the stimulator may be encapsulated bybiomaterials such as polydimethylsiloxane (PDMS) or epoxy-titanium.Coating the stimulator with PDMS or similar materials not only canprotect the telemetric CMOS circuit, but also offer enhanced adhesionproperty to the nerve or nearby tissues.

FIG. 8 is another embodiment of the present invention that involves awireless, battery-less and lead-less stimulator capable of applyingthermal energy to stimulate targeted ganglion 500. Such implantablestimulator comprises a CMOS chip 600 that includes: power rectifier 610,voltage regulator 620, thermal source driver 630, thermalsource/conductor 640, RF signal receiver 650, micro-controller 660,transmitter 670, analog digital converter 680, physiological sensor 690,and electrical sensor 691. The stimulator is wirelessly powered by powersource 300 of remote controller 400 via coil 200. The CMOS chip 600 isconfigured for bilateral data transmission in which receiver 301 mayalso receive signals from transmitter 670.

The thermal source driver 630 may convert electrical energy totemperature differentials. Specifically, the thermal source driver 630may contain a Peltier cell or module that converts electrical voltage tothermal energy. Thermal energy may be in either cooling or heating form.The thermal source driver 630 applies thermal energy to the ganglion 500via a plurality of thermal conductors 640. Thermal energy is alsoprecisely controlled by the micro-controller 660 to avoid permanentlydamaging the ganglion.

FIG. 9 is yet another embodiment of the present invention that disclosesa wireless, battery-less and lead-less stimulator capable of applyingoptical irradiation to stimulate targeted ganglion 500. The implantablestimulator comprises a CMOS chip 700 that includes: power rectifier 710,voltage regulator 720, light source driver 730, a plurality of diodes740, RF signal receiver 750, micro-controller 760, transmitter 770,analog digital converter 780, physiological sensor 790, and electricalsensor 791. The stimulator is wirelessly powered by power source 300 ofremote controller 400 via coil 200. The CMOS chip 700 is configured forbilateral data transmission in which receiver 301 may also receivesignals from transmitter 770.

The light source driver 730 may be a laser diode diver that deliversprecise current to the plurality of diodes 740 for optical stimulationof the ganglion. Diode laser is preferred in nerve stimulation becausethey are small, low-intensity and require relative little power. In onepreferred embodiment, a low-power pulsed infrared laser driver may beused to drive the diodes. Other types of light source driver may also beemployed in the stimulator of the present invention as long as safe andreproducible nerve action potential can be evoked.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalents included within the spirit and scope ofthe appended claims.

What is claimed is:
 1. A method for treating a disease of a patientdiagnosed with at least one of hyperhidrosis and Raynaud's phenomenon,the method comprising: positioning an implantable, lead-less andbattery-less stimulator proximate to T-2 ganglion and T-3 ganglion alongthe sympathetic nerve chain wherein the stimulator is configured to bewirelessly controlled and charged; monitoring the bio impedance of theT-2 ganglion and T-3 ganglion and the electrical states of thestimulator; transmitting the monitored bio impedance and electricalstates to a remote controller; applying pulsed radiofrequency in asinusoidal waveform to the T-2 ganglion and T-3 ganglion via thestimulator; and adjusting the stimulation parameters of the pulsedradiofrequency with the remote controller based on the monitored bioimpedance and electrical states until the symptoms of the disease havebeen alleviated.
 2. The method of claim 1, wherein the stimulationparameters comprise pulse frequency, pulse width duration, currentamplitude, voltage amplitude, duty cycle and waveform of the pulsedradio frequency.
 3. The method of claim 1, wherein the electrical statesof the stimulator comprise voltage level, current amplitude, impedanceand temperature of the stimulator.
 4. The method of claim 1, furthercomprising the step of monitoring the physiological states of thepatient.
 5. The method of claim 4, wherein the physiological states ofthe patient comprise heart rate, body and tissue temperatures, bloodpressure and blood oxygen level of the patient.
 6. The method of claim4, further comprising the step of adjusting the stimulation parametersof the pulsed radiofrequency based on the monitored physiologicalstates.
 7. The method of claim 4, further comprising the step oftransmitting the monitored physiological states to the remotecontroller.
 8. The method of claim 7, further comprising the step ofadjusting the stimulation parameters of the pulsed radiofrequency withthe remote controller based on the monitored physiological states. 9.The method of claim 4, further comprising the step of clamping ameasuring means to a blood vessel near the T-2 ganglion and T-3 ganglionalong the sympathetic nerve chain.
 10. The method of claim 1, furthercomprising the step of wirelessly control and charge the stimulator witha remote controller.
 11. The method of claim 10, wherein the remotecontroller wirelessly controls and charges the stimulator by near fieldinductive coupling, electro-magnetic induction coupling, resonateinductive coupling, capacitive coupling, light or radio frequencyspectrum charging.
 12. The method of claim 1, wherein positioning thestimulator proximate to T-2 ganglion and T-3 ganglion along thesympathetic nerve chain further comprises suturing the stimulator to theT-2 ganglion and T-3 ganglion or its nearby tissues.
 13. The method ofclaim 1, wherein the pulsed radiofrequency is applied between about 10KHz to about 10 MHz.
 14. The method of claim 1, wherein the pulseradiofrequency amplitude is applied between about 1 volt to about 60volts.
 15. The method of claim 1, wherein the pulse radiofrequency widthis applied between about 0.1 microseconds to about 500 microseconds.